Dual Inhibition of ID1 and ID3 in Targeting Pulmonary Fibrosis
Idiopathic pulmonary fibrosis (IPF) remains one of the most challenging respiratory diseases to treat. Characterized by progressive scarring of lung tissue, IPF leads to declining lung function and limited survival, with current therapies only slowing disease progression. New strategies that directly interrupt the cellular drivers of fibrosis are urgently needed.
A recent study by Samar A Antar et al (2026) sheds light on a promising therapeutic target: the simultaneous inhibition of ID1 and ID3 – two proteins involved in regulating cell behavior. The study found that ID1 and ID3 are significantly upregulated in both human patients and animal models of pulmonary fibrosis, particularly within fibroblasts. This suggests they play a central role in driving the disease process.
Dual Targeting of ID1 and ID3
While previous work examined these proteins individually, this study highlights an important insight: ID1 and ID3 compensate for each other. Targeting just one is not enough, both must be inhibited simultaneously to see meaningful effects.
Using genetic and pharmacological approaches, the researchers demonstrated that dual inhibition of ID1/ID3:
- Reduces fibroblast proliferation and migration
- Prevents differentiation into fibrosis-driving myofibroblasts
- Improves lung function in preclinical models using the flexiVent
Notably, treated mice showed improved flexiVent lung compliance and reduced collagen deposition – key indicators of functional recovery.
Mechanism: Cell Cycle and MEK/ERK Pathways
The study also uncovers how ID1 and ID3 exert their effects through both cell cycle and MEK/ERK pathways. ID1/ID3 promote fibroblast proliferation by upregulating genes like cyclins and CDK1, which drive cell division. Inhibiting these proteins disrupts this process, slowing fibroblast expansion. These proteins also activate the MEK/ERK pathway, a key regulator of cell differentiation. Blocking ID1/ID3 reduces this signaling, preventing fibroblasts from transforming into collagen-producing myofibroblasts. Together, these mechanisms strike at two core drivers of fibrosis: uncontrolled cell growth and pathological differentiation.
Conclusion
This work positions ID1 and ID3 as central regulators of fibroblast activation and interesting targets for intervention. By simultaneously disrupting cell cycle progression and profibrotic signaling, dual inhibition offers a multifaceted approach to slowing or potentially reversing lung fibrosis. As research continues, strategies that refine delivery (such as lung-targeted gene therapy) and minimize off-target effects will be key to translating these findings into clinical success.
Reference:
Antar, S.A., et al. Theranostics (2026). Simultaneous inhibition of ID1 and ID3 mitigates fibroblast activation via cell cycle and MEK/ERK pathways in pulmonary fibrosis. 16(11):6081-6098. doi:10.7150/thno.127118
May, 2026
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